Early Life Stress (ELS) is a known risk factor for major depressive disorder (MDD). How this risk is expressed at the level of specific neural pathways is unknown. This Project will test the overarching hypothesis that depression at the brain systems-level involves selective dysfunction of highly integrated limbic-cortical-striatal circuits responsible for mediating adaptive motivational, emotional, and cognitive responses to everyday life events. The proposed studies will test two hypotheses: (1) that specific neural responses in depression-specific pathways are altered by exposure to ELS; and (2) that it is these specific neural system alterations that constitute a vulnerability factor for MDD. The planned imaging studies build and extend two main observations from the current CCNMD funding period: (1) abuse, neglect and parental loss at critical time points in early child development are associated with sensitized autonomic, endocrine and behavioral responses to various emotional stimuli; and (2) such sensitization appears to convey increased risk for the later development of various mood disorders, most notably major depressive disorder (MDD). In this context, the role of ELS as a depression risk factor will be examined by characterizing brain regions and associated pathways in a select subset of female subjects with well-characterized ELS from Project 0007. Neuroimaging probes of mood, self-reference and salience processing previously validated in healthy subjects will be used to investigate vulnerability and variability effects in patient subgroups stratified by MDD and ELS. The specific imaging probes were selected on the basis of their theoretical relevance to primary symptoms of major depression and their reliability in effecting changes in those brain regions most consistently identified across published structural MRI, post-mortem morphometric, resting state PET, and fMRI activation studies of depressed patient populations. In addition, the specific paradigms and planned analytic strategies have also been shown to be sensitive to depression subgroups, illness state and trait differences as well as treatment effects. The infrastructure provided by the CCNMD cores, combined with the careful characterization of demographic, genetic, endocrine and behavioral markers in ELS exposed subjects in Project 0007 provide an unparalleled opportunity to systematically test the impact of ELS on selective pathways of known involvement in MDD. These studies will provide critical data for defining brain-biomarkers of MDD vulnerability that may lead to potential pre-symptomatlc stress tests for individual at high illness risk. Identification of consistent neural systems correlates of MDD subtypes will lay foundation for the future development of brain-based algorithms to optimize diagnosis and treatment selection in individual depressed patients.